Structural Complexities of Insulin Receptor Signaling
Michael Stowell
Professor, University of Colorado - Boulder
Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes and inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality. We have determined he cryo-EM structure of the IR bound to a peptide mimetic (S597) that stabilizes a novel extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Furthermore, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. This peptide is a potential therapeutic for the treatment of rare congenital insulin resistance diseases such as Donohue syndrome and Rabson-Mendenhall syndrome. We will describe the novel functional and structural features of the S597/IR complex as well as that of several S597 analogs with improved activities.
Michael Stowell received his Ph.D. in Chemistry and Biophysics from the California Institute of Technology and was a Postdoctoral Scientist at the MRC – Laboratory of Molecular Biology, Cambridge England and the Biophysics Department of Kyoto University, Japan. Dr. Stowell has authored publications in the fields of synthetic organic chemistry, mechanical engineering, structural biology, neurobiology, and biophysics. He is currently a professor in the department of Molecular, Cellular and Developmental Biology at CU Boulder, the Faculty Director of the CU Boulder EM Services Core, and a co-director of the NIH Funded CU Boulder Center for Cryo-ET (CCET).